FANCJ/BACH1 acetylation at lysine 1249 regulates the DNA damage response.
FANCJ/BACH1 acetylation at lysine 1249 regulates the DNA damage response.
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DOI：
10.1371/journal.pgen.1002786
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发表时间：
2012-07
期刊：
影响因子：
4.5
通讯作者：
Cantor SB
中科院分区：
文献类型：
--
作者：
Xie J;Peng M;Guillemette S;Quan S;Maniatis S;Wu Y;Venkatesh A;Shaffer SA;Brosh RM Jr;Cantor SB
BRCA 1通过与多种蛋白质（包括CtIP和FANCJ（也称为BRIP 1/BACH 1））相互作用来促进DNA修复。虽然CtIP在去乙酰化时促进DNA末端切除，但FANCJ在修复加工中的功能不太清楚。在这里，我们报告，FANCJ也乙酰化。阻止FANCJ在赖氨酸1249处的乙酰化不会干扰细胞在DNA链间交联（ICL）中存活的能力。然而，通过减少对重组的依赖来实现抗性。从机制上讲，FANCJ乙酰化促进修复和检查点信号传导所需的DNA末端加工。这一结论是基于以下发现：FANCJ及其乙酰化是响应于喜树碱（CPT）的稳健RPA焦点形成、RPA磷酸化和Rad 51焦点形成所需的。此外，阻止和模拟赖氨酸1249处的FANCJ乙酰化都破坏了FANCJ在检查点维持中的功能。因此，我们提出FANCJ乙酰化的动态调节对于稳健的DNA损伤反应、基于重组的处理和最终的检查点维持至关重要。BRCA 1-范可尼贫血（FA）通路是肿瘤抑制和细胞存活所必需的，特别是在用诱导DNA链间交联（ICL）的DNA损伤剂治疗后。通过BRCA-FA途径的ICL加工包括通过跨损伤合成促进同源重组（HR）和DNA损伤耐受。然而，关于BRCA-FA通路或这些ICL加工机制是如何调节的知之甚少。在这里，我们确定乙酰化作为BRCA-FA蛋白FANCJ的DNA损伤依赖性调节剂。赖氨酸1249处的FANCJ乙酰化通过组蛋白乙酰转移酶CBP的表达而增强，并且通过组蛋白脱乙酰酶HDAC 3或SIRT 1的表达而降低。此外，在用产生DNA损伤的试剂处理细胞后诱导内源性FANCJ上的乙酰化。与在细胞DNA修复期间调节FANCJ功能的这种翻译后事件一致，防止FANCJ乙酰化使ICL加工偏斜。细胞对HR因子Rad 54的依赖性降低，对跨损伤合成聚合酶polη的依赖性增加。我们的数据表明，FANCJ乙酰化有助于HR所需的DNA末端加工。此外，切除依赖性检查点的维持依赖于FANCJ乙酰化的动态调节。这些发现的含义是FANCJ乙酰化有助于BRCA-FA途径中的DNA修复选择。
BRCA1 promotes DNA repair through interactions with multiple proteins, including CtIP and FANCJ (also known as BRIP1/BACH1). While CtIP facilitates DNA end resection when de-acetylated, the function of FANCJ in repair processing is less well defined. Here, we report that FANCJ is also acetylated. Preventing FANCJ acetylation at lysine 1249 does not interfere with the ability of cells to survive DNA interstrand crosslinks (ICLs). However, resistance is achieved with reduced reliance on recombination. Mechanistically, FANCJ acetylation facilitates DNA end processing required for repair and checkpoint signaling. This conclusion was based on the finding that FANCJ and its acetylation were required for robust RPA foci formation, RPA phosphorylation, and Rad51 foci formation in response to camptothecin (CPT). Furthermore, both preventing and mimicking FANCJ acetylation at lysine 1249 disrupts FANCJ function in checkpoint maintenance. Thus, we propose that the dynamic regulation of FANCJ acetylation is critical for robust DNA damage response, recombination-based processing, and ultimately checkpoint maintenance. The BRCA1–Fanconi anemia (FA) pathway is required for both tumor suppression and cell survival, particularly following treatment with DNA damaging agents that induce DNA interstrand crosslinks (ICLs). ICL processing by the BRCA–FA pathway includes promotion of homologous recombination (HR) and DNA damage tolerance through translesion synthesis. However, little is known about how the BRCA–FA pathway or these ICL processing mechanisms are regulated. Here, we identify acetylation as a DNA damage–dependent regulator of the BRCA–FA protein, FANCJ. FANCJ acetylation at lysine 1249 is enhanced by expression of the histone acetyltransferase CBP and reduced by expression of histone deacetylases HDAC3 or SIRT1. Furthermore, acetylation on endogenous FANCJ is induced upon treatment of cells with agents that generate DNA lesions. Consistent with this post-translation event regulating FANCJ function during cellular DNA repair, preventing FANCJ acetylation skews ICL processing. Cells have reduced reliance on HR factor Rad54 and greater reliance on translesion synthesis polymerase polη. Our data indicate that FANCJ acetylation contributes to DNA end processing that is required for HR. Furthermore, resection-dependent checkpoint maintenance relies on the dynamic regulation of FANCJ acetylation. The implication of these findings is that FANCJ acetylation contributes to DNA repair choice within the BRCA–FA pathway.
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DOI：
10.1126/science.1203430
发表时间：
2011-06-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cotta-Ramusino C;McDonald ER 3rd;Hurov K;Sowa ME;Harper JW;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
16
作者：
Gong, Zihua;Kim, Ja-Eun;Leung, Charles Chung Yun;Glover, J. N. Mark;Chen, Junjie
通讯作者：
Chen, Junjie
影响因子：
3.4
作者：
Searle, Brian C.
通讯作者：
Searle, Brian C.
影响因子：
4.8
作者：
Naryzhny, SN;Lee, H
通讯作者：
Lee, H
影响因子：
30.8
作者：
Levitus, M;Waisfisz, Q;Joenje, H
通讯作者：
Joenje, H